title: Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1.
abstract: Disrupted-in-Schizophrenia-1 (DISC1), identified by positional cloning of a balanced translocation (1;11) with the breakpoint in intron 8 of a large Scottish pedigree, is associated with a range of neuropsychiatric disorders including schizophrenia. To model this mutation in mice, we have generated Disc1(tr) transgenic mice expressing 2 copies of truncated Disc1 encoding the first 8 exons using a bacterial artificial chromosome (BAC). With this partial simulation of the human situation, we have discovered a range of phenotypes including a series of novel features not previously reported. Disc1(tr) transgenic mice display enlarged lateral ventricles, reduced cerebral cortex, partial agenesis of the corpus callosum, and thinning of layers II/III with reduced neural proliferation at midneurogenesis. Parvalbumin GABAergic neurons are reduced in the hippocampus and medial prefrontal cortex, and displaced in the dorsolateral frontal cortex. In culture, transgenic neurons grow fewer and shorter neurites. Behaviorally, transgenic mice exhibit increased immobility and reduced vocalization in depression-related tests, and impairment in conditioning of latent inhibition. These abnormalities in Disc1(tr) transgenic mice are consistent with findings in severe schizophrenia.
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, United Kingdom. sanbing.shen@abdn.ac.uk
authors.forename: Sanbing
authors.initials: S
authors.lastname: Shen
authors.forename: Bing
authors.initials: B
authors.lastname: Lang
authors.forename: Chizu
authors.initials: C
authors.lastname: Nakamoto
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Jin
authors.initials: J
authors.lastname: Pu
authors.forename: Soh-Leh
authors.initials: SL
authors.lastname: Kuan
authors.forename: Christina
authors.initials: C
authors.lastname: Chatzi
authors.forename: Shuisheng
authors.initials: S
authors.lastname: He
authors.forename: Iain
authors.initials: I
authors.lastname: Mackie
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.forename: Karen L
authors.initials: KL
authors.lastname: Marquis
authors.forename: Mark
authors.initials: M
authors.lastname: Day
authors.forename: Orest
authors.initials: O
authors.lastname: Hurko
authors.forename: Colin D
authors.initials: CD
authors.lastname: McCaig
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
authors.forename: David
authors.initials: D
authors.lastname: St Clair
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D019417:Hindlimb Suspension / Q000379:methods; D007266:Inhibition, Psychological; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016501:Neurites / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010320:Parvalbumins / Q000378:metabolism; D010641:Phenotype; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D013550:Swimming
chemical_list: C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine